It is known that alkyl 1,4-dialkyl-3-alkoxycarbonyl-pyrrole-2-acetates, sometimes simply designated as pyrrole diesters, are useful as intermediates in the preparation of 5-aroylpyrrole-2-acetic acids and derivatives having analgesic and anti-inflammatory properties. It is also known that such compounds, although difficult to prepare because of the effect of other substituents in hindering substitution at the 4-position, can be synthesized, e.g., by condensing a chloromethyl alkyl ketone with a dialkyl acetone dicarboxylate and an alkylamine.
Carson's U.S. Pat. No. 3,752,826 and its divisions, U.S. Pat. Nos. 3,865,840 and 3,952,012, show that this condensation can be accomplished in an aqueous medium, although experience has revealed that the aqueous reaction leads to the formation of solid intermediates which are difficult to agitate and present problems in controlling the exothermic reaction that occurs when the intermediates are converted to the desired product.
Copending applications Ser. Nos. 137,231 and 137,250, filed Apr. 4, 1980, in the names of Michael J. Dagani and James T. F. Kao, respectively, show that the disadvantages of Carson's process can be overcome by the use of a halogenated hydrocarbon or an aromatic hydrocarbon as a co-solvent; and Mallinckrodt's UK Patent Application GB No. 2 034 304 A also teaches advantages of using an aqueous/organic medium for the reaction.
Further improvements in alkyl 1,4-dialkyl-3-alkoxycarbonylpyrrole-2-acetate syntheses are taught in copending applications Ser. No. 293,853, filed Aug. 18, 1981, in the name of Michael J. Dagani, and Ser. No. 317,156, filed Nov. 2, 1981, in the names of James T. F. Kao and Everett M. Marlett now U.S. Pat. Nos. 4,388,568 and 4,383,117, respectively. The former application discloses that the use of elevated temperatures to dehydrate the dihydroxypyrrolidine intermediate can obviate the need for the intermediate isolation and acidification steps that had previously been used in these syntheses. The latter application teaches that problems associated with the use of the reaction media formerly employed--specifically, the solids formation problem associated with the use of an aqueous medium and the feed control problems associated with the use of a two-phase aqueous/organic medium--can be avoided by contacting the reactants in a non-aqueous organic solvent and conducting the reaction in the absence of any added water.
Both the use of an aqueous/organic reaction medium and the use of an organic solvent are commercially-attractive means of preparing the pyrrole diesters. However, with the utilization of known techniques, reactions conducted in these media lead to yields no higher than about 72%, with somewhat lower yields being more typical. It would obviously be desirable to provide a means of increasing those yields.